Altria Altria Client Services James E. Dillard III Senior Vice President Regulatory Affairs
March 22, 2010
Ms. Cristi L. Stark Acting Executive Secretary Tobacco Products Scientific Advisory Committee Center for Tobacco Products Food and Drug Administration 9200 Corporate Boulevard, Room 110H Rockville, Maryland 20850
Re: March 30-31, 2010 Meeting of the Tobacco Products Scientific Advisory Committee
Philip Morris USA Inc. ("PM USA") 1 makes this submission in response to the Food and Drug Administration ("FDA") request for comments as stated in 75 Federal Register 9422.
As stated in § 907(e) of the FSPTCA2, the Tobacco Products Scientific Advisory Committee ("TPSAC") must submit a report and recommendation to FDA on the "issue of the impact of the use of menthol in cigarettes on the public health, including such use among children, African- Americans, Hispanics, and other racial and ethnic minorities." In conducting its review of menthol, the TPSAC shall address the considerations listed in § 907 (a)(3)(B)(i) and (b), which include:
(1) "[T]he risks and benefits to the population as a whole, including users and nonusers of tobacco products...;" (2) "[T]he increased or decreased likelihood that existing users of tobacco products will stop using such products;" (3) "[T]he increased or decreased likelihood that those who do not use tobacco products will start using such products;"
Altria• Client Services (ALCS) is making this submission on behalf of PM USA. ALCS provides certain services, including regulatory affairs, to the Altria family of companies. "We" is used throughout to refer to PM USA. 2 Family Smoking Prevention and Tobacco Control Act
Altria Client Services Inc. 615 Maury St. Richmond, Virginia 23224 (804) 335-2679 [email protected] (4) "[T]he countervailing effects of the tobacco product standard on the health of adolescent tobacco users, adult tobacco users, or nontobacco users, such as the creation of a significant demand for contraband or other tobacco products..."
FDA's decision-making and the TPSAC's review and recommendation related to the use of menthol in cigarettes should be science- and evidence-based to assure the credibility of the regulatory process. We recognize and support the important statutorily mandated role of the TPSAC in advising FDA (based on a fair and impartial assessment of the science) regarding the implementation of the FSPTCA. As such, we have raised concerns related to financial conflicts of interest and intellectual biases of some of the members of the TPSAC in a letter to Commissioner Margaret Hamburg and Dr. Lawrence Deyton. We look forward to working with a TPSAC as Congress intended — an impartial arbiter of the science. 3
Per our conversation on March 8, 2010, and as you requested, we are providing this limited submission summarizing our understandings from the published scientific literature related to menthol. We are happy to provide the TPSAC with a more extensive overview. Also, we understand that the second meeting of the TPSAC in the summer of 2010 will present an opportunity for PM USA and other tobacco manufacturers to provide additional menthol-related data for the TPSAC's consideration. To begin, PM USA agrees with the overwhelming medical and scientific consensus that cigarette smoking causes lung cancer, heart disease, emphysema and other serious diseases in smokers and is addictive. Smokers are far more likely to develop serious diseases, like lung cancer, than non- smokers. There is no safe cigarette. It can be very difficult to quit smoking, but this should not deter smokers who want to quit from trying to do so. To reduce the health effects of cigarette smoking, the best thing to do is to quit. This applies equally to menthol and non-menthol cigarettes. With regard to menthol, our analysis of the published scientific literature (summarized below) 4 concludes that menthol does not change these inherent health risks of cigarette smoking.
3 As stated in our comments to FDA's FSPTCA docket: . . . the establishment of the Tobacco Products Scientific Advisory Committee (TPSAC) is an important opportunity for FDA to promote a science-based regulatory agenda. We believe that technically-qualified, unbiased committee members who bring a wealth of diverse backgrounds, experiences, and opinions to the table should be selected for the TPSAC. Given the many complexities of tobacco regulation, broad, inclusive consultation and open-minded consideration of the scientific and other evidence will be the best way to develop appropriate regulations. Comments of PM USA and USSTC, Docket No. FDA-2009-N-0294, December 22, 2009, at 2. 4 A list of citations and references is attached to this submission.
2 A. BACKGROUND
In 2009, menthol cigarettes represented about 29% of cigarettes sold in the United States.
Based on estimates from the National Survey of Drug Use and Health (Substance Abuse and Mental Health Services Administration [SAMHSA], 2008) of adults 18 and over, self- reported5 menthol cigarette smoking is higher among African-American adult cigarette consumers (87% or 6 million adults) as compared to White adult cigarette consumers (25% or 10 million adults), Hispanic adult cigarette consumers (33% or 2 million adults) and all other adult cigarette consumers (32% or 1 million adults).
Recent estimates from the National Survey of Drug Use and Health (SAMHSA, 2008) of adults 18 and over suggest that overall prevalence of current adult cigarette consumers is roughly equal among African-Americans adults (27% or 7 million adults) and White adults (27% or 41 million adults), but higher than Hispanic adults (13% or 6 million adults) and the total adult population (20% or 3 million adults).
B. HUMAN USE - MENTHOL
• Menthol has a long history of safe use in foods.
Menthol has been approved for food use by the FDA [21 Code of Federal Regulations (CFR) 172.515 & 21 CFR 182.20], the Joint Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) (FAO/WHO 1999), and the Flavor and Extract Manufacturers Association (FEMA). FEMA has designated menthol as generally recognized as safe for its intended use as a flavoring (GRAS) (No.2665 GRAS List No. 3).
C. NON-CLINICAL TOXICITY TESTING - MENTHOL
• Scientific evidence demonstrates that menthol has limited toxicity in non-clinical toxicity testing.
A comprehensive toxicologic and dermatologic evaluation of menthol was recently published by the Research Institute for Fragrance Materials (RIFM) Expert Panel (Belsito, et al., 2008). A toxicologic review of menthol as a fragrance ingredient has also recently been published (Bhatia, et al., 2008). Menthol has a relatively low order of acute toxicity in rodents.
Long term inhalation studies using menthol vapor (0.087, 0.148, and 0.259 ppm; 6.75 hours/day for 71-79 days) in rats (Rakeiten, et aL, 1954) produced only mild, transient erythema of the conjunctiva, which disappeared after the animals were returned to their cages. No other effects were observed in these menthol-treated animals. An acute inhalation study in mice and rats (Goldstein, et al., 1976) was conducted with menthol (0.1 to 0.13 ug/L; 4 or 8 hour exposure) in combination with camphor eucalyptol and
5 Adults who report using cigarettes in the past 30 days; adult population numbers are rounded to the nearest million.
3 turpentine (as part of a colds preparation) and using radiolabeled Staphylococcus aureus which found no effect on mucociliary transport and phagocytic functions in the lungs of these animals.
Subchronic feeding studies in rats and mice indicate a No Observed Effect Level (NOEL) in both species of 7500 ppm (Mengs & Stotzem 1989; Uno, et al., 1994; Miyagawa, et al., 1995; Adams, et al., 1996). Long-term carcinogenicity feeding studies in rats and mice at concentrations up to 7500 ppm indicated slightly decreased body weights, but no treatment-related effects in any tissues examined, and concluded that menthol was not carcinogenic in rats or mice (U.S. National Cancer Institute [NCI],1979). Teratology studies found no effect of menthol administration in the mouse, rat, hamster or rabbit at the maximum administered doses of 185, 218, 405 and 425 mg/kg, respectively, or in the offspring thereof (Food and Drug Research Labs, 1973). These studies indicate that menthol does not possess teratogenic potential.
Negative results have been obtained in the Salmonella reverse mutation assay, sister chromatid exchange assay, chromosomal aberration studies, replicative DNA synthesis and L5178Y mouse lymphoma cell assays (FDA 1975; Andersen & Jensen 1984; Ishidate, et al., 1984; Ivett, et al., 1989; Murthy, et al., 1991; Uno, et al., 1994; Miyagawa, et al., 1995; Carneiro, et al., 1997; Hilliard, et al., 1998; Zeiger, et al., 1988). Positive in vitro genotoxicity of menthol is found only at high concentrations where it possesses significant cytotoxicity (Elia, et al., 1994; Storer, et al., 1996; Hartmann & Speit 1997). Overall, the weight of evidence suggests that menthol is not genotoxic.
D. NON-CLINICAL TOXICITY TESTING - MENTHOL CIGARETTES
• Scientific evidence demonstrates that menthol cigarettes do not result in increased toxicity in non-clinical toxicity testing compared to non-menthol cigarettes.
Four papers (Carmines, 2002; Roemer, et al., 2002; Rustemeier, et al., 2002; Vanscheeuwijck, et al., 2002) describe methods and assays (smoke chemistry, Salmonella mutagenicity, cytotoxicity and 90-day rodent inhalation) used to test the effect of a mixture of ingredients added to cigarettes. These studies were conducted in accordance with Good Laboratory Practice (GLP) guidelines. Menthol was included in this study in amounts up to 18,000 ppm (Carmines, 2002). Although changes in some mainstream tobacco smoke constituents occurred and the incidence of changes could be expected to occur based on statistical chance, the changes could not be traced to a specific ingredient and they were not accompanied by any toxicologically significant change in biological response in the in vitro or in vivo assays. A similar ingredient "mix" study with similar results was published by Baker, et al. (2004) and a comprehensive review of the effect of ingredients including menthol was published by Paschke, et al. (2002). In agreement with these studies, Coggins, et al. (1990) and Gaworski, et al. (1997) reported no differential effects of menthol cigarettes (as compared with non-menthol cigarettes) in rodent subchronic inhalation studies using various exposure concentrations. Furthermore, menthol was evaluated as part of four comparative two-stage, inbred SENCAR mouse skin painting bioassays (Gaworski, et al., 1999) that showed no effect. Comparisons of
4 heated versus burned tobacco with actual use levels of menthol in cigarettes showed no effect of menthol on mutagenicity (Salmonella reverse mutation, chromosomal aberration and sister chromatid exchange assays) of cigarette smoke condensates (Doolittle, et al., 1989; Doolittle, et al., 1990a; Doolittle, et al., 1990b; Lee, et al., 1989; Lee, et al., 1990) as compared to non-menthol cigarettes. It is important to remember that menthol transfers intact into smoke from cigarettes with little if any pyrolysis or combustion (Jenkins, et al., 1970). Furthermore, in these studies Jenkins, et al. (1970) found that menthol was distributed in mainstream cigarette smoke (28.9%) and sidestream cigarette smoke (44.3%) with 26.9% in the cigarette butt (total recovery = 100.1%).
E. HUMAN USE - MENTHOL CIGARETTES - EXPOSURE TO SMOKE
• Scientific evidence suggests smoking menthol cigarettes produces no consistent effect on exposure to smoke.
Multiple Constituents - Description of the PM USA Total Exposure Study The Total Exposure Study (TES) was a stratified, multi-center, cross-sectional study that included 3,585 adult smokers and 1,077 non-smokers from 31 states (39 sites) across the U.S. The TES was designed to estimate exposure to tobacco smoke (Roethig, et al., 2009) and to investigate the relationship between exposure and machine-derived tar yield (Mendes, et al., 2009). The TES study received Institutional Review Board approval and was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Informed consent was obtained from each participant and blood samples, 24-hour urine sample and butts from cigarettes smoked were collected. Several well established biomarkers of exposure to smoke and biomarkers of potential harm were measured. The participants also completed a questionnaire, and smoking topography was measured. The TES study included approximately 1,100 menthol (of which 448 were African-American) and 2,400 non-menthol adult smokers (of which 166 were African- American).
Using data from the TES, Wang, et al. (2009) investigated cigarettes per day (CPD), nicotine equivalents (NE) (mg/24hours), NE per cigarette (mg/cig), serum cotinine (ng/mL) and carboxyhemoglobin (COHb % saturation) in menthol and non-menthol adult smokers. Descriptive statistics using unadjusted data were provided for completeness. Wilcoxon Rank Sum analysis of the unadjusted results showed a number of small, but statistically significant differences.
After adjusting for factors in the ANCOVA models, no statistically significant effects were observed for menthol or for interactions of menthol with race and gender on NE/24 h, COHb, serum cotinine and NE/cigarette (Wang, et al., 2009).
Total Particulate Matter (TPM) One study (Jarvik, et al., 1994) found no increase in cigarette smoke TPM delivered or retained in the respiratory tract when menthol cigarettes were compared to non-menthol cigarettes, using the same machine-derived tar yield category.
5 Carbon Monoxide (CO) In eight studies that evaluated the potential relationship between CO exposure and mentholation in cigarettes, six studies (Caskey, et al., 1993; Heck, 2009; McCarthy, et al., 1995; Pickworth, et al., 2002; Pritchard, et al., 1999; Wang, et al., 2009) reported no effect, one study reported an increase associated with mentholation (Clark, et al., 1996), and one study (Ahijevych, et al., 1996) reported a decrease. In a separate study, Jarvik, et al. (1994) reported that an increase in CO exposure was observed with menthol; however, the statistical analysis shown did not support this claim, as discussed in Werley, et al. (2007).
Cotinine In four studies that evaluated the potential relationship between cigarettes with menthol and cotinine levels, two studies (Ahijevych & Parsley, 1999; Clark, et al., 1996) reported an increase in urinary cotinine excretion with menthol (statistical significance not reported), one (Ahijevych, et al., 1996) found a non-significant decrease and the latest study (Heck, 2009) found no statistically significant differences in urinary cotinine levels between menthol and non-menthol smokers regardless of race.
Nicotine Metabolism One study (Benowitz, et al., 2004) found no evidence that smoking menthol cigarettes accelerated nicotine metabolism as compared to smoking non-menthol cigarettes; rather, smoking of menthol cigarettes was reported to decrease nicotine metabolism. Recent work has also highlighted the genetic variations in the primary enzyme (CYP2A6) responsible for metabolizing nicotine to cotinine (Levi, et al., 2007; Mwenifumbo & Tyndale, 2007; Mwenifumbo & Tyndale, 2009; Ray, et al., 2009; Swan, et al., 2004; Swan, et al., 2005; Swan & Lessov-Schlaggar, 2009). The metabolite ratio of trans -3'- hydroxy cotinine to cotinine is a widely accepted phenotypic marker of CYP2A6 activity (Nakajima, et al.,1996, Dempsey, et al., 2004). This ratio was not found to be significantly different between menthol and non-menthol smokers in the PM USA Total Exposure Study (Wang, et al., 2009) as well as in other studies (Ho, et al., 2009).
NNAL-Glucuronide/Free NNAL Ratio Carmella, et al. (1995) proposed that the urinary level of 4-(methylnitrosamino)-1-(3- pyridy1)-1-butanone (NNK) metabolites (e.g., the ratio of 4-(methylnitrosamino)-1-(3- pyridy1)-1-butanol (NNAL) glucuronides to free NNAL) might serve as a biomarker for a smoker's ability to detoxify NNK. Richie, et al. (1997) hypothesized that the NNAL- glucuronide/free NNAL ratio may exhibit phenotypic differences related to lung cancer and that African-Americans have lower NNAL-glucuronide/free NNAL ratios than Whites. Importantly, genetic polymorphisms in the glucuronidation of NNAL have been identified (Hukkanen, et al., 2005). A recent study, Muscat, et al. (2009), reported that the NNAL-glucuronide/free NNAL ratio was significantly lower in menthol versus non- menthol smokers (regardless of race). However, the investigators found that this ratio was 34% lower in White smokers of menthol cigarettes (statistically different from White non- menthol smokers) and 22% lower in African-American menthol cigarette smokers (not statistically different from African-American non-menthol smokers). Variations in NNAL-glucuronide/free NNAL ratios, however, were not found to correlate with lung
6 cancer risks among three different ethnic/racial populations, raising uncertainties about the functional significance of this metabolic parameter (Derby, et al., 2009).
• Scientific evidence suggests smoking menthol cigarettes produces no consistent effects on human puffing and inhalation behavior.
Number of Puffs Of seven studies that address smoking topography, five studies (Ahijevych, et al., 1996; Caskey, et al., 1993; Miller, et al., 1994; Pickworth, et al., 2002; St. Charles, et al., 2009) reported no effect of menthol and two studies (Jarvik, et al., 1994; McCarthy, et al., 1995) reported a reduced number of puffs in menthol cigarette smokers.
Puff Volume Of six studies that measured the effects of cigarettes with menthol on puff volume, three studies (Ahijevych, et al., 1996; Miller, et al., 1994; St. Charles, et al., 2009) found no effect, two studies (Jarvik, et al., 1994; McCarthy, et al., 1995) found a decrease in puff volume associated with menthol and one study (Ahijevych & Parsley, 1999) found an increase.
Depth of Inhalation It has been suggested that the depth of inhalation is different in menthol cigarette smokers compared with non-menthol smokers. While this has not been determined using objective measures of depth of inhalation, Jarvik, et al. (1994) reported, based on a respiratory retention study, that no significant differences were observed in the depth of inhalation between menthol and non-menthol smokers.
F. HUMAN USE - MENTHOL CIGARETTES — IMPACT ON DISEASE RISKS
• Epidemiological evidence suggests no effect of menthol on smoking-related disease risks.
To date, thirteen epidemiological studies comparing smoking-related disease outcomes between menthol versus non-menthol cigarette smokers have been published (Hebert & Kabat, 1988; Hebert & Kabat, 1989; Kabat & Hebert, 1991; Kabat & Hebert, 1994; Sidney, et al., 1995; Friedman, et al., 1998; Carpenter, et al., 1999; Brooks, et al., 2003; Stellman, et al., 2003; Jockel, et al., 2004, Pletcher, et al., 2006; Murray, et al., 2007; Etzel, et al., 2008). The disease outcomes evaluated include smoking-related cancers such as those of the lung, esophagus, oropharynx, upper aerodigestive tracts, pancreas, kidney, urinary tract and uterine cervix as well as coronary calcification, pulmonary function decline and mortality from coronary heart disease, cardiovascular disease, lung cancer and all causes.
Twelve of the thirteen studies reported no significant differences between menthol versus non-menthol smokers for any of the health outcomes evaluated. One of the studies reported a statistically elevated risk [relative risk (RR) 1.45; 95%CI: 1.03-2.02] for lung cancer among men who smoked menthol cigarettes compared with men who smoked non-
7 menthol cigarettes (Sidney, et al., 1995). However, no significant menthol-related effect was observed in this study among women. The same investigators conducted a follow-up investigation using the same study population to determine if increases related to smoking menthol cigarettes in other smoking-related cancers would be observed (Friedman, et al., 1998). No increases related to smoking menthol cigarettes for cancer risk were observed for the sites evaluated which included upper aerodigestive, pancreas, renal adenomacarcinoma, other urinary tract, uterine cervix and all smoking-related sites. The finding of an increased risk of lung cancer associated with menthol cigarettes reported by Sidney, et al. (1995) was not replicated in six subsequent studies (Carpenter, et al., 1999; Brooks, et al., 2003; Stellman, et al., 2003; Jockel, et al., 2004; Murray, et al., 2007; Etzel, et al., 2008) addressing possible effects of menthol on lung cancer risks.
• Scientific evidence does not support a role for menthol in the smoking- related health disparities observed between African-Americans and Whites.
Compared to Whites, lung cancer risk is higher in African-American men but not African- American women ( U.S. Department of Health and Human Services [HHS], 1998; Fagan, et al., 2007a; NCI 1997; Abidoye, et al., 2007; Jemal, 2008a). Menthol smoking prevalence is higher among African-American women than it is in both African-American men and White women (Allen & Unger 2007; Moolchan 2004). Moreover, menthol smoking prevalence among Latinos is higher than it is among Whites (Giovino, et al., 2004) while their lung cancer risk is notably less (Haiman, et al., 2006). Not all smoking- related diseases are higher in African-Americans compared to Whites (CDC MMWR 2002a; CDC 2002b; Mannino, et al., 2000). The disparity in smoking-related lung cancer mortality among African-American versus White men is narrowing (Delancey, et al., 2008). In fact, lung cancer rates are declining at a faster rate among African-Americans than they are among Whites (Jemal, et al., 2009) despite the fact that menthol cigarette use remains substantially higher among African-Americans compared to Whites (SAMHSA, 2009).
The collective body of epidemiological studies suggests no effect of menthol in cigarettes on smoking-related disease risk. Several possible explanations exist for the health disparities discussed above. First, never-smoking African-Americans have a higher background incidence of lung cancer compared with White never smokers (Thun, et al., 2008). Therefore, it is possible that smoking could be adding to an underlying difference in background lung cancer susceptibility between African-American and White smokers. Second, racial and gender specific trends in lung cancer risk reflect historical differences in smoking patterns (HHS, 1998). In particular, smoking prevalence has historically been higher among African-American men than it has been among White men (NCI, 1997). Third, comparisons of smoking-related health risks between African-Americans and Whites are confounded by, and may be accounted for by, differences in socioeconomic status (Devesa & Diamond, 1983 ; Baguet, et al., 1991 ; Jemal, et al., 2008b).
• Findings from the PM USA Total Exposure Study suggest no effect of smoking menthol cigarettes on biomarkers of potential harm.
8 PM USA Total Exposure Study - Biomarkers of Potential Harm (BOPH) The effect of smoking menthol cigarettes on BOPH, specifically, von Willebrand factor, microalbumin, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, white blood cells, fibrinogen, C-reactive protein, monocyte chemotactic protein-1, interleukin-6, 8-epi-prostaglandin-F2a, 8-isoprostaglandin Fla-VI, platelets, fibrinogen, 11-dehydrothromboxane-B2, triglycerides, low density lipoprotein (LDL) cholesterol, total cholesterol, high density lipoprotein (HDL) cholesterol, oxidized low- density lipoprotein, lipoprotein-associated phospholipase A2, glucose, total adiponectin, and leptin was investigated in adult smokers. Menthol had no statistically significant effect on any of the BOPH (Frost-Pineda, et al., 2010).
G. HUMAN USE — MENTHOL CIGARETTES — IMPACT ON SMOKING BEHAVIOR
• Based on currently used methods, studies indicate that menthol does not increase nicotine dependence.
Nicotine Dependence The terms "addiction" and "dependence" are often used interchangeably, and may have different definitions when used by scientists, policy makers and the general public. Nicotine dependence is often used in the clinical and research context to diagnose a disorder or measure the prevalence of patterns of cigarette smoking behavior. The two most widely used measures are the DSM-IV criteria (American Psychiatric Association, 2000) and the Fagerstrom Test for Nicotine Dependence (FTND) (Heatherton, et al., 1991). These methods have been extensively reviewed (Shadel, et al., 2000) and have also been the subject of critiques (DiFranza, et al., 2010; NCI, 2009).
Despite the difference in the prevalence of menthol smoking in different racial/ethnic groups, the 1998 Surgeon General's Report concluded that "Persons of all racial/ethnic backgrounds are vulnerable to becoming addicted to nicotine, and no consistent differences exist in the overall severity of addiction or symptoms of addiction across racial/ethnic groups." (HHS, 1998). Studies with experimental menthol cigarettes with no nicotine did not show any pharmacological effects (Ahijevych & Garrett, 2004; Pritchard, et al., 1999). Two recent studies (Luo, et al., 2008; Muscat, et al., 2009) which directly examine FTND scores and the use of menthol cigarettes, found no increased odds of dependence. A study by Luo, et al. (2008) found that African-Americans had significantly lower mean FTND scores, smoked significantly less cigarettes per day, were significantly less likely to smoke when sick and were more likely to be able to refrain from smoking where it is prohibited. Muscat, et al. (2009) showed that there was no significant association between high FTND scores and the use of menthol cigarettes (odds ratio, 1.1; 95% confidence interval, 0.6-2.0). Using other "indicators of dependence," Hyland, et al. (2002) reported no consistent association between menthol use and dependence both in their overall and race-based analyses.
Studies of adolescents are inconsistent in how they classify smoking status, menthol status, and how dependence is measured. Hersey, et al. (2006) reported that adolescent
9 menthol smokers "had significantly higher scores on a scale of nicotine dependence;" however, the scores are not reported. Wackowski and Delnevo (2007) reported that menthol smokers had higher odds of endorsing two of four dependence related statements and no difference for the other two statements. DiFranza, et al. (2004) reported no difference between menthol and non-menthol adolescent smokers on the Hooked on Nicotine Checklist. In addition, Collins and Moolchan (2006) reported shorter time to first cigarette among menthol smokers, but found no difference in FTND scores.
Total Exposure Study The Total Exposure Study included FTND scores for 1,104 menthol and 2,481 non- menthol adult smokers. Mean FTND scores were similar for menthol (4.5) and non- menthol (4.6) cigarette smokers. African-American menthol (4.0; 95% CI 3.83-4.19) and non-menthol smokers (4.1; 95% CI 3.78-4.35) had lower mean scores compared to White menthol (4.9; 95% CI 4.71-5.07) and non-menthol (4.6; 95% CI 4.56-4.74) cigarette smokers. Muhammad-Kah, et al. (2010) reported that menthol status had no statistically significant effect on any single item of FTND or on the overall scores; menthol smokers had no increased odds of having higher FTND scores as compared to non-menthol smokers (odds ratio, 0.97; 95% confidence interval, 0.83 -1.13); and that these results add to the existing body of evidence that menthol does not increase nicotine dependence.
• Research on the effect of menthol cigarette use on smoking cessation outcomes is characterized by null and inconsistent findings.
The majority of studies testing the effect of menthol cigarette smoking on cessation outcomes has produced null (Cropsey, et al., 2009; Fagan, et al., 2007b; Hyland, et al., 2002; Murray, et al., 2007; Muscat, et al., 2002) or mixed results (Gandhi, et aL, 2009; Gundersen, et al., 2009; Okuyemi, et al., 2007; Okuyemi, et al., 2003; Pletcher, et al., 2006). When mixed results have been obtained, they often are only marginally significant and typically occur only for some measures, under certain conditions and for certain smokers. For example, in the Pletcher, et al. (2006) study, use of menthol cigarettes was unrelated to quitting among smokers who reported trying to quit. However, menthol cigarette use appeared marginally associated with a lower likelihood of trying to quit in the first place (p = 0.11) and a lower likelihood of sustained abstinence (p = 0.06). Additionally, menthol cigarette use was associated with a higher risk of relapse. In the Okuyemi, et al. (2003) study, abstinence rates appeared to vary by age and treatment condition. At 6 weeks' follow-up, among those less than 50 years old, only 24.9% of menthol smokers were abstinent compared to 44.4% of non-menthol smokers. Among those 50 years old or older, abstinence rates of menthol and non-menthol cigarette smokers did not differ. Likewise, at 6 weeks' follow-up, non-menthol smokers who received bupropion were more likely to have quit than their menthol smoking counterparts. On the other hand, the 6-week abstinence rates of menthol and non-menthol smokers did not differ in the placebo condition. Also, the overall 6-month abstinence rates of menthol and non-menthol smokers did not differ.
A few studies have yielded only marginally significant results, some pointing to an association between menthol cigarette smoking and poorer cessation outcomes (Foulds, et
10 al., 2006; Okuyemi, et al., 2004) and at least one pointing to an association between menthol cigarettes and improved cessation outcomes (Fu, et al., 2008).
There are important methodological issues underlying the studies of menthol cigarette use and cessation, some of which were raised earlier by Heck (2010). As one example, most of the studies pertinent to this topic have been conducted in clinical settings with non- representative samples. Only two studies have entailed analyses of data from representative samples of adults, and they yielded different results. Gundersen, et al. (2009) analyzed data from the 2005 U.S. National Health Interview Survey. They found that African-Americans and Hispanics who reported smoking menthol cigarettes were less likely to be former smokers than their regular cigarette smoking counterparts. On the other hand, Whites who reported using menthol cigarettes were more likely to be former smokers than their regular smoking counterparts. Fagan, et al. (2007b) analyzed data for 18 to 30 year old smokers from the national 2003 Tobacco Use Special Cessation Supplement to the Current Population Survey. In contrast to Gundersen, et al. (2009), these investigators suggested that it is not menthol cigarette smokers who are less likely to quit, but daily smokers who report smoking no usual type of cigarette — menthol or non- menthol.
• Research on the topic of menthol cigarette use and smoking initiation is limited and constrained by measurement issues.
Individuals initiate smoking both as adolescents and adults (SAMHSA, 2009b). According to recent estimates, 56.6% of adult current smokers initiated smoking under the age of 18 (Schoenborn & Adams, 2010). Youth smoking rates have declined significantly since peak levels in the mid-1990's (Johnson, et al., 2009). The prevalence of past month cigarette smoking among 12 to 17 year olds in 2008 was 9.1% overall and 10.6%, 7.9% and 5.0% among non-Hispanic White, Hispanic, and non-Hispanic Black youth, respectively (SAMHSA, 2009).
There is no single reason why some adolescents engage in risky behaviors, such as the use of cigarettes and other tobacco products. Instead, data and published literature suggest a range of potential factors — environmental, social and personal — related to underage smoking (Bricker, et al., 2009; Flay, et al., 1999; O'Loughlin, et al., 2009; Turner, et al., 2004). Menthol cigarettes have not been identified as one of these risk factors. 6
Some research, however, suggests that rates of menthol cigarette use are higher among younger, less established smokers compared to their older, more established counterparts (Hersey, et al., 2006; SAMHSA, 2009a). To date, research to identify and test potential explanations for these findings has not been published. Some have speculated that menthol cigarettes facilitate initiation by "mask[ing] the harshness and discomfort of inhaling smoke" (Kreslake, et al., 2008). Contrary to this speculation, DiFranza, et al. (2004) found no significant differences between menthol and non-menthol cigarettes in
6 A comprehensive review of the myriad of genetic, social and environmental risk factors for tobacco use and dependence was recently presented in the National Cancer Institute's Tobacco Control Monograph 20 (NCI, 2009). Menthol was not identified as a contributing factor to tobacco use in this report.
11 respondents' subjective responses to their first inhaled cigarette. Among the 7 th grade respondents in their study, there were no significant differences in self-reported measures of irritation, nausea, dizziness and relaxation between those who smoked menthol versus non-menthol cigarettes. In addition, there were no significant differences in self reports of positive response to the smoking experience and wanting to smoke again in the future between those who smoked menthol versus non-menthol cigarettes. DiFranza, et. al. (2004) reported, "Reactions to the initial smoking experience were unrelated to gender or cigarette brand, strength or mentholation." Other researchers have concluded that the explanation for the higher rate of menthol cigarette use among younger individuals is unclear and requires additional research (Heck, 2010; Hersey, et al., 2006; Wackowski & Delnevo, 2007).
In addition to the limited number of published studies on menthol cigarette use and smoking initiation, current understanding is constrained by important measurement issues. For example, underage and less established smokers are prone to inconsistencies when reporting the brands and types of cigarettes they smoke. Some researchers have raised such issues in the course of their work (Hersey, et al., 2006; Wackowski & Delnevo, 2007). These issues, however, remain largely unaddressed and unresolved. For the most part, the available studies have relied on secondary analyses of primary research, which were not conducted with the primary intention of testing questions regarding menthol cigarette use. More clearly refined and consistently applied measurement and analytic strategies will help achieve a better understanding of this topic.
If you have any questions regarding the information provided in this submission, please do not hesitate to contact me.
Sincerely,
James E. Dillard III
12 REFERENCES'
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